It is known that 4-(1H-imidazol-4-ylmethyl)piperidine (nonproprietary name: immepip) has histamine H3 agonistic activity and it is useful as histamine H3-positive control reagent, and also is commercially available. Additionally, it is known that 4-(1H-imidazol-4-ylethyl)piperidine (known as VUF4929) has histamine H3 antagonistic activity.
A process for manufacturing these imidazole derivatives is known, which comprises reacting 5-lithio salt of 1,2-di-protected-imidazole (e.g. 2-trimethylsilyl-N,N-dimethyl-1H-imidazole sulfonamide) with 4-pyridine-carbaldehyde to introduce a pyridin-4-ylhydroxymethyl group onto the 5-position of the imidazole nucleus, acetylating the hydroxyl group thereof, reducing it under a high pressure, and then deprotecting it (R. C. Vollinga, et al., J. Med. Chem. 37, 332-333, 1994 and WO 9506037).
However, this process has some disadvantages, such that it needs multiple reaction steps, and needs long reaction time under a high pressure in the reducing reaction, and so on. Additionally, it is a problem that the overall yield is very low, only 20% from the starting imidazole compound.
Alternatively, there is also known a process which includes reaction of imidazol-4-ylmethyl chlorides with the Grignard reagents prepared from N-protected-4-chloro-piperidine in the presence of a cupper salt, and then deprotection of the reaction product (WO 9312107). However, this process has problems, such that it needs to use a lot of heavy metals, and so forth.
Accordingly, it is desirable to develop an improved process for producing the above imidazole derivatives more easily and in higher yield.